SUMOylation-Dependent Repression of BIRC7 by DNMT3a Suppresses Papillary Thyroid Carcinoma Progression.

Papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy, and while most patients respond well to standard therapies, a subset displays aggressive behavior, including lymph node metastasis and recurrence. The molecular mechanisms underlying PTC progression remain incompletely understood. Here, we identify baculoviral IAP repeat-containing 7 (BIRC7) as a pro-oncogenic factor upregulated in PTC tissues, particularly in metastatic tumors. Bioinformatic analysis of The Cancer Genome Atlas (TCGA) dataset and validation in clinical samples revealed a strong inverse correlation between BIRC7 expression and DNA methylation levels at its promoter. Mechanistically, we demonstrate that the DNA methyltransferase DNMT3a directly binds to the BIRC7 promoter and represses its transcription via promoter methylation. Pharmacological inhibition or siRNA-mediated knockdown of DNMT3a leads to hypomethylation and transcriptional activation of BIRC7. Importantly, we show that DNMT3a undergoes SUMOylation, which negatively regulates its binding to the BIRC7 promoter. Inhibition of SUMOylation enhances DNMT3a chromatin occupancy and reduces BIRC7 expression. Functionally, BIRC7 promotes PTC cell proliferation and migration, while DNMT3a overexpression reverses these phenotypes in vitro and suppresses BIRC7-mediated tumor growth in vivo. Our study uncovers a previously unrecognized SUMOylation-dependent epigenetic regulatory axis wherein DNMT3a represses BIRC7 transcription. These findings establish BIRC7 as an epigenetically regulated oncogene in PTC and suggest that modulating DNMT3a SUMOylation may represent a novel therapeutic strategy for aggressive PTC.